Gadolinium-linked nanoclusters

Abstract

The invention relates to nanocluster compositions and uses thereof. Specifically, the invention relates to gadolinium-linked nanocluster compositions and their use in diagnosis and prognosis of diseases. The nanocluster compositions of the invention are effective in enhancing the payload of a gadolinium and thereby increasing the longitudinal relaxivity of each particle in the cluster.

1 . A composition comprising a porous cluster of nanoparticles, each nanoparticle in said cluster linked to a gadolinium ion, wherein said each nanoparticle is further linked to at least one other nanoparticle in said cluster. 
     
     
         2 . The composition of  claim 1 , wherein said composition is effective in enhancing the payload of a gadolinium ion. 
     
     
         3 . The composition of  claim 1 , wherein said cluster exhibits the longitudinal relaxivity of more than 100 mM −1 S −1  per particle. 
     
     
         4 . The composition of  claim 1 , wherein the hydrodynamic diameter of each nanoparticle is about 150 nm. 
     
     
         5 . The composition of  claim 1 , wherein at least one nanoparticle of said cluster is linked to a ligand, wherein the ligand is specific for a pre-selected marker. 
     
     
         6 . The composition of  claim 1 , wherein said nanoparticle is a polymer. 
     
     
         7 . The composition of  claim 1 , wherein said nanoparticle is a dendrimer. 
     
     
         8 . The composition of  claim 7 , wherein said dendrimer is a PAMAM dendrimer. 
     
     
         9 . The composition of  claim 1 , wherein said nanoparticle is a polymersome. 
     
     
         10 . The composition of  claim 1 , wherein said nanoparticle is a polymer, a dendrimer, a polymersome, a liposome, a macromolecule, a peptide, a protein, a chelating agent, a nucleic acid, a polylysine, a dextran, or a combination thereof. 
     
     
         11 . The composition of  claim 1 , wherein the porosity of said cluster is between about 1 and about 85% (v/v). 
     
     
         12 . The composition of  claim 1 , comprising no less than about 50 gadolinium ions. 
     
     
         13 . The composition of  claim 1 , wherein said nanoparticle is conjugated to said gadolinium ion. 
     
     
         14 . The composition of  claim 1 , wherein said composition comprises a cross-linking agent that links said each nanoparticle to said atleast one other nanoparticle. 
     
     
         15 . The composition of  claim 1 , wherein said composition comprises a cross-linking agent that links said each nanoparticle to said chelated gadolinium ion; said chelated gadolinium ion to another chelated gadolinium ion; or combinations thereof. 
     
     
         16 . The composition of  claim 14  or  15 , wherein said cross-linking agent is a homobifunctional crosslinker, a heterobifunctional cross-linker, a linear polymer, a branched polymer, a nanoparticle, a nucleic acid, a peptide, a protein, or a combination thereof. 
     
     
         17 . The composition of  claim 14  or  15 , wherein said cross-linking agent is NHS-PEG-NHS. 
     
     
         18 . The composition of  claim 14  or  15 , wherein said cross-linking agent is a thiol-ene chemistry linker. 
     
     
         19 . A magnetic resonance imaging agent comprising the composition of  claim 1 . 
     
     
         20 . A blood pool agent comprising the composition of  claim 1 . 
     
     
         21 . An imaging agent for macrophage infiltration comprising the composition of  claim 1 . 
     
     
         22 . A method for producing a cluster of nanoparticles, comprising the steps of:
 providing a plurality of nanoparticles;   cross-linking each nanoparticle with at least one other nanoparticle;   labeling each nanoparticle with a gadolinium ion; and   functionalizing said cluster with a target agent.   
     
     
         23 . The method of  claim 22 , the step of cross-linking is performed in presence of a cross-linking agent. 
     
     
         24 . The method of  claim 23 , wherein the molar ratio of said nanoparticle and said cross-linking agent is approximately 50:1. 
     
     
         25 . The method of  claim 22 , wherein the cross-linked cluster of nanoparticles is effective in enhancing the payload of a gadolinium ion. 
     
     
         26 . The method of  claim 22 , wherein said cluster exhibits R1 relaxivity of more than 100 mM −1 S −1  per particle. 
     
     
         27 . The method of  claim 22 , wherein the hydrodynamic diameter of each nanoparticle of said cluster is about 150 nm. 
     
     
         28 . The method of  claim 22 , wherein at least one nanoparticle of said cluster is linked to a ligand, wherein the ligand is specific for a pre-selected marker. 
     
     
         29 . The method of  claim 22 , wherein said nanoparticle is a polymer. 
     
     
         30 . The method of  claim 22 , wherein said nanoparticle is a dendrimer. 
     
     
         31 . The method of  claim 30 , wherein said dendrimer is a PAMAM dendrimer. 
     
     
         32 . The method of  claim 22 , wherein said nanoparticle is a polymersome. 
     
     
         33 . The method of  claim 22 , wherein said nanoparticle is a polymer, a dendrimer, a polymersome, a liposome, a macromolecule, a peptide, a protein, a chelating agent, a nucleic acid, a polylysine, a dextran, or a combination thereof. 
     
     
         34 . The method of  claim 22 , wherein the porosity of said cluster is between about 1 and about 85% (v/v). 
     
     
         35 . The method of  claim 22 , wherein said cluster comprises no less than about 50 gadolinium ions. 
     
     
         36 . The method of  claim 22 , wherein said nanoparticle is conjugated to said gadolinium ion. 
     
     
         37 . A method of obtaining a magnetic resonance image (MRI), in a subject, comprising administering to said subject a composition comprising a porous cluster of nanoparticles, each nanoparticle in said cluster linked to a gadolinium ion and a targeting ligand, wherein said each nanoparticle is further linked to at least one other nanoparticle in said cluster, whereby the targeting ligand is specific for a marker of a disease in said subject. 
     
     
         38 . The method of  claim 37 , whereby the targeting ligand is coupled covalently to said nanoparticle. 
     
     
         39 . The method of  claim 37 , whereby the targeting ligand is a small molecule, a peptide, a natural binding partner, another protein ligand, an antibody or their combination. 
     
     
         40 . The method of  claim 37 , whereby the marker is a marker of a cancer, inflammation, an autoimmune disease, a cardiovascular disease, apoptosis or their combination. 
     
     
         41 . The method of  claim 40 , whereby the cancer marker is a Transferrin receptor, c-MET, αv-β3 integrins, EGFR, Her2/neu, PSA, a member of the MUC-type mucin family, a member of the epidermal growth factor receptor (EGFR) family, a carcinoembryonic antigen (CEA), a MAGE (melanoma antigen) gene family antigen, a T/Tn antigen, a hormone receptor, a Cluster Designation/Differentiation (CD) antigen, a tumor suppressor gene, a cell cycle regulator, an oncogene, an oncogene receptor, a proliferation marker, an adhesion molecule, a proteinase involved in degradation of extracellular matrix, a malignant transformation related factor, a human carcinoma antigen, a member of the vascular endothelial growth factor (VEGF) receptor family, a glycoprotein antigen, a DF3 antigen, a 4F2 antigen, a MFGM antigen, or their combination. 
     
     
         42 . The method of  claim 40 , whereby the cardiovascular disease marker is VCAM-1, integrin glcyoprotein IIb/IIIa, myosin, e-selectin, or their combination. 
     
     
         43 . The method of  claim 40 , whereby the apoptosis marker is synaptotagmin I, phophatidylserine or their combination. 
     
     
         44 . A contrast agent for magnetic resonance (MR), computerized tomography (CT), or X-ray imaging, comprising a porous cluster of nanoparticles, each nanoparticle in said cluster linked to a gadolinium ion and a targeting ligand, wherein said each nanoparticle is further linked to at least one other nanoparticle in said cluster. 
     
     
         45 . A blood pool agent, comprising a porous cluster of nanoparticles, each nanoparticle in said cluster linked to a gadolinium ion, wherein said each nanoparticle is further linked to at least one other nanoparticle in said cluster. 
     
     
         46 . An imaging agent for macrophage infiltration comprising: a porous cluster of nanoparticles, each nanoparticle in said cluster linked to a gadolinium ion and a targeting ligand, wherein said each nanoparticle is further linked to at least one other nanoparticle in said cluster. 
     
     
         47 . An agent for visualizing a cell comprising: a porous cluster of nanoparticles, each nanoparticle in said cluster linked to a gadolinium ion and a targeting ligand, wherein said each nanoparticle is further linked to at least one other nanoparticle in said cluster. 
     
     
         48 . The composition of  claim 1 , further comprising a drug. 
     
     
         49 . The composition of  claim 1 , further comprising a radionuclide coupled to said cluster.